The goal of the current application is to develop molecular models of agonist and antagonist binding sites within the transmembrane (TM) domain of the human sweet taste receptor. We have selected for our studies on the sweetener cyclamate and the antagonist lactisol. We will identify the binding pockets in the sweet taste receptor for sweeteners, and sweet taste inhibitors, that are known to bind in the TM domain, by molecular docking and will test via mutagenesis studies. The model receptor and the docked complexes will serve as initial structures for molecular dynamics simulations in an attempt to understand the underlying mechanism of activation and inhibition of the sweet taste response. The molecular mechanism of agonists and antagonists binding and activation/inhibition of the sweet taste receptor may lead to rational structure based design of novel non-caloric sweeteners, which will aid in the fight against obesity and diabetes. Understanding the taste response mechanisms may also be important for developing new treatment methods for patients with taste malfunctions. [unreadable] [unreadable]